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Molecular and Cellular Biology, January 2001, p. 678-689, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.678-689.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Jak3 Selectively Regulates Bax and Bcl-2 Expression To Promote T-Cell Development

Renren Wen,1 Demin Wang,1 Catriona McKay,1 Kevin D. Bunting,2,dagger Jean-Christophe Marine,1,3,Dagger Elio F. Vanin,2 Gerard P. Zambetti,1,4 Stanley J. Korsmeyer,5 James N. Ihle,1,3 and John L. Cleveland1,4,*

Departments of Biochemistry1 and Experimental Hematology2 and Howard Hughes Medical Institute,3 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Biochemistry, University of Tennessee, Memphis, Tennessee 381634; and Department of Cancer Immunology and AIDS and Howard Hughes Medical Institute, Dana Farber Cancer Institute, Boston, Massachusetts 021155

Received 29 August 2000/Returned for modification 16 October 2000/Accepted 27 October 2000

Jak3-deficient mice display vastly reduced numbers of lymphoid cells. Thymocytes and peripheral T cells from Jak3-deficient mice have a high apoptotic index, suggesting that Jak3 provides survival signals. Here we report that Jak3 regulates T lymphopoiesis at least in part through its selective regulation of Bax and Bcl-2. Jak3-deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates. Notably, up-regulation of Bax in Jak3-deficient T cells is physiologically relevant, as Jak3 Bax double-null mice have marked increases in thymocyte and peripheral T-cell numbers. Rescue of T lymphopoiesis by Bax loss was selective, as mice deficient in Jak3 plus p53 or in Jak3 plus Fas remained lymphopenic. However, Bax loss failed to restore proper ratios of peripheral CD4/CD8 T cells, which are abnormally high in Jak3-null mice. Transplantation into Jak3-deficient mice of Jak3-null bone marrow transduced with a Bcl-2-expressing retrovirus also improved peripheral T-cell numbers and restored the ratio of peripheral CD4/CD8 T cells to wild-type levels. The data support the concepts that Jak kinases regulate cell survival through their selective and cell context-dependent regulation of pro- and antiapoptotic Bcl-2 family proteins and that Bax and Bcl-2 play distinct roles in T-cell development.

* Corresponding author. Mailing address: Department of Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2398. Fax: (901) 525-8025. E-mail: john.cleveland{at}stjude.org.

dagger Present address: Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, Md.

Dagger Present address: Instituto Europeo di Oncologia, Milan, Italy.

Molecular and Cellular Biology, January 2001, p. 678-689, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.678-689.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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